Apparatus for Manufacturing Biochip and Method for Manufacturing Biochip Tip Array Module

ABSTRACT

An apparatus of manufacturing a biochip and manufacture method of biochip tip array. The invention provides an apparatus for manufacturing a biochip from a substrate. The apparatus comprises a tip array, a reservoir tank and a conduit connecting the tip array and the reservoir tank. When the substrate is placed over the tip array, the agent in the reservoir tank can be applied to the substrate by moving upward and downward the reservoir tank with respect to the tip array.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to apparatus for manufacturing a biochip, and more particularly to an apparatus for manufacturing a biochip with high density array tips.

2. Description of the Related Art

Diagnostic arrays are used in biomedical testing, research, and others to identify unknown samples of materials such as DNA, protein, antibodies and the like. In a typical diagnostic process, a diagnostic test strip array is prepared by depositing a number of discrete drops of liquids at known points on a solid substrate to form a predetermined pattern (array) of diagnostic probes. A plurality of probes has a known tendency to react with a particular substance.

High throughput screening methods for synthesizing (e.g., using combinatorial chemistry methods) and screening large numbers of these compounds for biological and physicochemical properties are desired. For example, a conventional method uses an array of pins dipped into the wells of a microtitre plate, for transferring an array of samples to a substrate, such as a porous membrane.

U.S. Pat. No. 5,445,934 discloses an apparatus for preparation of a substrate containing a plurality of sequences. Photoremovable groups are attached to a surface of a substrate. Selected regions of the substrate are exposed to light so as to activate the selected areas. A monomer is provided to the substrate to bind at the selected areas. The process is repeated using a variety of monomers until sequences of a desired length are obtained.

U.S. Pat. No. 5,658,802 (Hayes et al.) teaches arrays of electromechanical dispensers to form extremely fine drops of fluid and locate them precisely on substrate surfaces in miniature arrays, wherein a positioning support such as an X-Y table, moves the dispensing devices and substrate surfaces relative to each other to locate the drops on the substrates. The valving scheme, however, is cumbersome and requires purging each time a switch is made to a different reagent. This wastes time and reagent and is more expensive to build, since a network of valves and tubing must be provided.

U.S. Pat. No. 5,807,522 uses a specially designed mechanical robot, which produces a probe spot on the microarray by dipping a pin head into a fluid containing an off-line synthesized DNA and then spotting it onto the slide at a predetermined position. Because a microarray contains a very large number of different probes, this technique, although highly flexible, is very slow. Although the speed can be employing multiple pin-heads and spotting multiple slides before washing can increase the speed, production throughput remains very low.

Therefore, it is necessary to develop a novel method and apparatus of manufacturing a biochip array.

BRIEF SUMMARY OF THE INVENTION

Apparatuses for manufacturing biochips are provided. An exemplary embodiment of an apparatus for manufacturing a biochip from a substrate comprises a tip, a reservoir tank, and a conduit connecting the tip and the reservoir tank. When the substrate is placed over the tip, an agent in the reservoir tank can be applied to the substrate by moving upward and downward the reservoir tank with respect to the tip array.

Another exemplary embodiment of an apparatus for manufacturing a biochip from a substrate comprises a tip array, a reservoir tank for storing an agent, a conduit connecting the tip and the reservoir tank, and a pressure controller connecting to the reservoir tank to control the pressure of the reservoir tank.

Methods of for manufacturing a biochip tip array module are also provided. An exemplary embodiment of a method comprises the following steps. A substrate is provided. A photoresist layer is formed on the substrate. First and second exposures are performed to the photoresist layer with a first and a second photo-mask respectively. The exposed photoresist layer is then developed to form a photoresist pattern thereon, wherein the photoresist pattern has a plurality of photoresist pillars arranged in an array. A metal layer is formed on the substrate outside the photoresist pillars to form a metal structure. The photoresist pillars and the substrate are removed to leave the metal structure for forming a tip array module, wherein the tip array module comprises a plurality of tips arranged in an array.

A detailed description is given in the following embodiments with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be more fully understood by reading the subsequent detailed description and examples with references made to the accompanying drawings, wherein:

FIG. 1 is a schematic diagram of an apparatus for manufacturing a biochip according to an embodiment of the invention.

FIGS. 2 a-2 h are cross sections showing a method of manufacturing a biochip tip array module according to an embodiment of the invention.

FIG. 3 is a schematic diagram of producing probe spots by moving the reservoir tank upward.

FIG. 4 is a schematic diagram of moving the reservoir tank downward after producing probe spots.

FIG. 5 is a schematic diagram of biochip with probe spots.

FIG. 6 shows the dimension of a probe spot of an agent.

FIG. 7 is a schematic diagram of an apparatus of manufacturing a biochip according to another embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best-contemplated mode of carrying out the invention. This description is made for the purpose of illustrating the general principles of the invention and should not be taken in a limiting sense. The scope of the invention is best determined by reference to the appended claims.

Referring to FIG. 1, the apparatus of manufacturing a biochip of the invention comprises a tip array 110, a reservoir tank 130, and a conduit 150 connecting the tip 110 and the reservoir tank 130. The tip array 110 comprises a plurality of tips 111 arranged in an array. The tip 111 has an inlet 113 and an outlet 115, and an agent is transported to a substrate (such as biochip) via the tip to produce an agent spot thereof. The tip can be formed by electroforming or machining. Suitable material of the tip can be metal, ceramic, or polymer.

The reservoir tank 130 comprises a reservoir plate 131 with a plurality of cavities 133 storing various agents. The reservoir tank can be formed by electroforming or machining. The reservoir tank can be made of metal (such as Ni, Co, Au), ceramic, or polymer.

The inlet 113 of the tip 111 is connected to the reservoir plate 131 via conduit 150, wherein the reservoir tank and the conduit have the same or different inner diameter. The agent stored in the reservoir tank 130 is transported from the conduit 150 to the tip array 110.

FIGS. 2 a-2 h are cross sections showing an embodiment of a method for manufacturing a biochip tip array module. Referring to FIG. 2 a, a photoresist layer 202 is formed on a substrate 201. The substrate can comprise Si, Ge, Cu or combinations thereof, such as a silicon substrate. Referring to FIGS. 2 b and 2 c, the photoresist layer 202 are subjected to first and second exposures with a first and a second photo-mask respectively, forming a photoresist pattern having a plurality of lower and higher photoresist pillars, wherein the photoresist pillars are arranged in an array.

Referring to FIG. 2 e, a metal layer is formed on the substrate 201 outside the photoresist pillars to form a metal structure 206. The metal layer can comprise Ni, Co, Au, or combinations thereof and be formed by electroplating, depositing or machining. Referring to FIGS. 2 f and 2 g, the photoresist pillars and the substrate 201 are removed to remain the metal structure to form a tip array module 200, wherein the tip array module 200 comprises a plurality of tips arranged in an array, wherein the tip array module 200 comprises an inlet 207 and an outlet 208. The outer diameter of the outlet 208 can be 50˜500 μm, preferably 300 μm. FIG. 2 h is a three-dimensional schematic diagram of the tip array module 200.

Referring to FIG. 3, the reservoir tank 130 comprises a reservoir plate 131 with a plurality of cavities 133 storing various agents. The agent can flow from the reservoir tank 130 to the tip array 110 via the conduit 150.

The steps for fabricating a biochip employing the apparatus for manufacturing a biochip of the invention are described in the following. First, a substrate is disposed and contact on the tip array 110, and the reservoir tank 130 is lifted higher than the tip array, wherein the height difference N therebetween is preferably 5cm. Because the reservoir tank 130 is located at a higher elevation with respect to the tip array 110, the agent 180 stored in the reservoir tank 130 can flow from the reservoir talk 130 to the tip array 110 via the conduit 150. Due to the capillary attraction between the substrate 170 and the tip 111, the agent 180 is applied to the substrate to form agent spots, rather than leaking out from the inlet 115. Referring to FIG. 4, after forming the agent spots on the substrate 170, the reservoir tank 130 is moved upward to be located at a lower elevation with respect to the tip array 110, wherein there is a height difference Y between the reservoir tank 130 and the tip array 110.

Referring to FIG. 5, the obtained biochip has a plurality of agent spots arranged in an array. The agent spots are separated by a specific distance from each other, preventing overlapping. Referring to FIG. 6, the agent spot can has a diameter of about 100 μm.

Referring to FIG. 7, in another embodiment of the invention, the apparatus of manufacturing a biochip further comprise a pressure controller 190 to force the agent 180 stored in the reservoir tank 130 flowing toward the tip 111. Namely, the pressure controller 190 controls the location of the agent 180 in the conduit 150. The the pressure controller 190 increases the pressure of the tank 130 to force the agent 180 to flow toward the tip and form a plurality of agent spots on the substrate 170. After forming the agent spots, the pressure of the tank 130 is reduced by the pressure controller 190, obtaining a biochip.

Accordingly, the invention provides an apparatus for manufacturing a biochip, capable of reducing cost and time required for mass production, suitable for use in the manufacture of biochips.

While the invention has been described by way of example and in terms of preferred embodiment, it is to be understood that the invention is not limited thereto. To the contrary, it is intended to cover various modifications and similar arrangements (as would be apparent to those skilled in the art). Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements. 

1. An apparatus for manufacturing a biochip from a substrate, comprising: a tip; a reservoir tank; and a conduit connecting the tip and the reservoir tank, when the substrate is paced over the tip, an agent in the reservoir tank can be applied to the substrate by moving upward and downward the reservoir tank with respect to the tip array.
 2. The apparatus as claimed in claim 1, wherein the tip is disposed on a tip array substrate.
 3. he apparatus as claimed in claim 2, wherein the tip array substrate comprises a plurality of tips arranged in an array.
 4. The apparatus as claimed in claim 1, wherein electroforming or machining forms the tip.
 5. The apparatus as claimed in claim 1, wherein the tip comprises metal, ceramic, or polymer.
 6. The apparatus as claimed in claim 1, wherein electroforming or machining forms the reservoir tank.
 7. The apparatus as claimed in claim 1, wherein the reservoir tank is comprises metal, ceramic, or polymer.
 8. The apparatus as claimed in claim 1, wherein the reservoir tank comprises a reservoir plate with a plurality of cavities storing various agents.
 9. The apparatus as claimed in claim 1, wherein the reservoir tank is moved upward to be located at a higher elevation with respect to the tip.
 10. The apparatus as claimed in claim 1, wherein the inner diameter of the reservoir tank is the same as the conduit.
 11. The apparatus as claimed in claim 1, wherein the reservoir tank and the conduit have different inner diameters.
 12. An apparatus of manufacturing a biochip from a substrate, comprising: a tip array; a reservoir tank for storing an agent; a conduit connecting the tip and the reservoir tan; and a pressure controller connecting to and controlling the pressure of the reservoir.
 13. The apparatus as claimed in claim 12, wherein the tip array substrate comprises a plurality of tips arranged in an array.
 14. The apparatus as claimed in claim 13, wherein electroforming or machining forms the tip.
 15. The apparatus as claimed in claim 12, wherein the tip comprises metal, ceramic, or polymer.
 16. The apparatus as claimed in claim 12, wherein electroforming or machining forms the reservoir tank.
 17. The apparatus as claimed in claim 12, wherein the reservoir tank is made of metal, ceramic, or polymer.
 18. The apparatus as claimed in claim 12, wherein the reservoir tank comprises a reservoir plate with a plurality of cavities storing various agents.
 19. The apparatus as claimed in claim 12, wherein the inner diameter of the reservoir tank is the same as the conduit.
 20. The apparatus as claimed in claim 12, wherein the reservoir tank and the conduit have different inner diameters.
 21. The apparatus as claimed in claim 12, wherein the pressure controller adjusts the agent location of the tip.
 22. A method for manufacturing a biochip tip array module, comprising: providing a substrate; forming a photoresist layer on the substrate; subjecting a first exposure to the photoresist layer with a first photo-mask; subjecting a second exposure to the photoresist layer with a second photo-mask; developing the substrate to form a photoresist pattern thereon, wherein the photoresist pattern has a plurality of photoresist pillars arranged in an array; forming a metal layer on the substrate outside the photoresist pillars to form a metal structure; and removing the photoresist pillars and the substrate to leave the metal structure to form a tip array module, wherein the tip array module comprises a plurality of tips arranged in an array.
 23. The method as claimed in claim 22, wherein the substrate comprises Si, Ge, Cu or combinations thereof.
 24. The method as claimed in claim 22, wherein the metal layer comprises Ni, Co, Au, or combinations thereof.
 25. The method as claimed in claim 22, wherein the metal layer is formed by electroplating, depositing or machining. 